Association of a presenilin 1 S170F mutation with a novel Alzheimer disease molecular phenotype

Alessandra Piccini, Gianluigi Zanusso, Roberta Borghi, Cristiana Noviello, Salvatore Monaco, Roberta Russo, Gianluca Damonte, Andrea Armirotti, Matteo Gelati, Renzo Giordano, Pamela Zambenedetti, Claudio Russo, Bernardino Ghetti, Massimo Tabaton

Research output: Contribution to journalReview article

41 Scopus citations

Abstract

Objective: To report an ataxic variant of Alzheimer disease expressing a novel molecular phenotype. Design: Description of a novel phenotype associated with a presenilin 1 mutation. Setting: The subject was an outpatient who was diagnosed at the local referral center. Patient: A 28-year-old man presented with psychiatric symptoms and cerebellar signs, followed by cognitive dysfunction. Severe β-amyloid (Aβ) deposition was accompanied by neurofibrillary tangles and cell loss in the cerebral cortex and by Purkinje cell dendrite loss in the cerebellum. A presenilin 1 gene (PSEN1) S170F mutation was detected. Main Outcome Measures: We analyzed the processing of Aβ precursor protein in vitro as well as the Aβ species in brain tissue. Results: The PSEN1 S170F mutation induced a 3-fold increase of both secreted Aβ42 and Aβ40 species and a 60% increase of secreted Aβ precursor protein in transfected cells. Soluble and insoluble fractions isolated from brain tissue showed a prevalence of N-terminally truncated Aβ species ending at both residues 40 and 42. Conclusion: These findings define a new Alzheimer disease molecular phenotype and support the concept that the phenotypic variability associated with PSEN1 mutations may be dictated by the Aβ aggregates' composition.

Original languageEnglish (US)
Pages (from-to)738-745
Number of pages8
JournalArchives of Neurology
Volume64
Issue number5
DOIs
StatePublished - May 1 2007

ASJC Scopus subject areas

  • Arts and Humanities (miscellaneous)
  • Clinical Neurology

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    Piccini, A., Zanusso, G., Borghi, R., Noviello, C., Monaco, S., Russo, R., Damonte, G., Armirotti, A., Gelati, M., Giordano, R., Zambenedetti, P., Russo, C., Ghetti, B., & Tabaton, M. (2007). Association of a presenilin 1 S170F mutation with a novel Alzheimer disease molecular phenotype. Archives of Neurology, 64(5), 738-745. https://doi.org/10.1001/archneur.64.5.738